Impairment of stromelysin-1 transcriptional activity by promoter mutations in high microsatellite instability colorectal tumors

Colorectal tumorigenesis is characterized by the sequential inactivation of a series of tumor suppressor genes (microsatellite-stable tumors) and genetic or epigenetic alterations in mismatch repair genes in nonpoliposic hereditary tumours and 13% to 15% of sporadic colorectal cancer [high microsate...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2005-05, Vol.65 (9), p.3811-3814
Main Authors: MORAN, Alberto, INIESTA, Pilar, DE JUAN, Carmen, GARCIA-ARANDA, Cristina, DIAZ-LOPEZ, Antonio, BENITO, Manuel
Format: Article
Language:English
Subjects:
Antineoplastic agents
Base Sequence
Biological and medical sciences
Colorectal Neoplasms - enzymology
Colorectal Neoplasms - genetics
DNA-Binding Proteins - genetics
Down-Regulation
Enzyme Activation
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Gene Transfer Techniques
Humans
Matrix Metalloproteinase 3 - biosynthesis
Matrix Metalloproteinase 3 - genetics
Matrix Metalloproteinase 9 - metabolism
Medical sciences
Microsatellite Repeats - genetics
Molecular Sequence Data
Mutation
Pharmacology. Drug treatments
Plasmids - genetics
Promoter Regions, Genetic - genetics
Transcription Factors - genetics
Transcriptional Activation - genetics
Tumors
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Summary:Colorectal tumorigenesis is characterized by the sequential inactivation of a series of tumor suppressor genes (microsatellite-stable tumors) and genetic or epigenetic alterations in mismatch repair genes in nonpoliposic hereditary tumours and 13% to 15% of sporadic colorectal cancer [high microsatellite instability (MSI-H) tumors]. We hypothesized a molecular mechanism for MSI-H colorectal tumors related to matrix metalloproteinase 3 (MMP-3) promoter mutations, down-regulation of MMP-3 expression, and impairment of MMP-9 activation. We have now analyzed the 2.2-kb full MMP-3 promoter to assess the mutation distribution. The mutations found are restricted to the polymorphic region that includes the zinc-binding protein (ZBP-89) binding element. To show that these alterations were the cause of the low expression of this gene, we have generated three constructs with different MMP-3 promoters (wild type and two mutants) and we have expressed them in SW480 human colorectal cells. The basal transcriptional activity of wild-type MMP-3 promoter was much higher than the mutants activity. In addition, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced transcriptional activity of wild-type MMP-3 promoter was 10-fold higher than the mutants activity. Dexamethasone inhibited the basal transcriptional activity of wild-type MMP-3 promoter and of the two mutants found in the MSI-H subgroup of colorectal tumors. Significantly, dexamethasone almost completely blunted the TPA-induced effect on wild-type MMP-3 promoter transcriptional activity and on the mutants, even below their basal activity. Our data show that mutations found in the polymorphic region of the MMP-3 promoter from MSI-H colorectal tumors impair its basal and induced transcriptional activity, which may contribute to their better clinical outcome.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-04-4442